Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.671
Filtrar
2.
Infect Dis Poverty ; 9(1): 21, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32046780

RESUMO

BACKGROUND: Plasmodium falciparum malaria is endemic in the southern sahelian zone of Mauritania where intense internal and trans-border human and livestock movement occurs. The risk of importation and spread of drug-resistant parasites need to be regularly assessed in this region. The objective of the study was to assess the recent malaria situation near the Mauritania-Mali border. METHODS: Between February 2015 and December 2017, patients with fever or history of fever during the previous 48 h, presenting at the health centre of Kobeni city, were screened for malaria using a rapid diagnostic test (RDT) and microscopic examination of blood smears. The diagnosis was later confirmed by PCR. Cohen's kappa statistics was used to estimate the degree of agreement between diagnostic methods. Fisher's exact test was used to compare proportions. The odds ratio was calculated to measure the association between the use of bed nets and malaria infection. RESULTS: A total of 2326 febrile patients (mean age, 20.2 years) were screened for malaria. The presence of malaria parasites was detected by RDT and microscopy in 53.0% and 49.3% of febrile patients, respectively, and was confirmed by PCR in 59.7% (45 missing data). Of 1361 PCR-positive samples, 1205 (88.5%) were P. falciparum, 47 (3.5%) P. vivax, and 99 (7.3%) P. falciparum-P. vivax mixed infection. Malaria transmission occurred mostly during and shortly after the rainy season. The annual rainfall was relatively low in 2016 (267 mm) and 2017 (274 mm), compared to 2015 (448 mm), and coincided with a decline in malaria prevalence in 2016-2017. Although 71.8% of febrile patients reported to possess at least one bed net in the household in our questionnaire, its reported use was not protective against malaria infection (odds ratio: 1.1, 95% CI: 0.91-1.32). CONCLUSIONS: Our study confirmed that P. falciparum is the dominant species in the sahelian zone and that malaria transmission is seasonal and associated with rainfall in this zone. The application of the current national policy based on rapid and reliable malaria diagnosis, case management with artemisinin-based combination therapy, intermittent preventive treatment for pregnant women, distribution and use of long-lasting insecticide impregnated bed nets, and the planned introduction of seasonal malaria chemoprevention for all children under 6 years old is expected to sustainably reduce malaria transmission in this zone.


Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/epidemiologia , Malária Vivax/epidemiologia , Adolescente , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Coinfecção/diagnóstico , Coinfecção/tratamento farmacológico , Coinfecção/epidemiologia , Testes Diagnósticos de Rotina/métodos , Quimioterapia Combinada , Feminino , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Malária Vivax/diagnóstico , Malária Vivax/tratamento farmacológico , Masculino , Mauritânia/epidemiologia , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Estações do Ano
3.
Gene ; 736: 144414, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32006594

RESUMO

Development of drug resistance in P. falciparum is one of the major problems associated with malaria treatment. Parasite genetic factors such as single nucleotide polymorphisms (SNPs) and copy number variations (CNV) have shown their role in drug resistance. Most of the studies have focused on the role of SNPs and drug resistance in parasite. However, it has also been shown that CNV is associated with adaptation and drug resistance in parasite. Hence, exploration of copy number polymorphism in essential genes of P. falciparum and their role in anti-malarial resistance is important. This review provides the recent information related to genetic profile of CNV marker in plasmepsin and other genes associated with drugresistanceinP. falciparum. It may be suggested that CNVs in plasmepsin genes are the major driver of piperaquine resistance. Moreover, CNVs in pfcrt and pfmdr1genes appear to play important role in adaptation and hence survival of the parasite. It may be hypothesized that targeting of CNV formation in the parasite could be beneficial for breakdown of its adaption in response to drug pressure.


Assuntos
Antimaláricos/farmacologia , Variações do Número de Cópias de DNA/genética , Resistência a Medicamentos/genética , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Polimorfismo de Nucleotídeo Único/genética , Animais , Humanos , Proteínas de Protozoários/genética
4.
Parasitol Int ; 74: 101919, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31015034

RESUMO

BACKGROUND: Malaria parasites have developed resistance to most of the known antimalarial drugs in clinical practice, with reports of artemisinin resistance emerging in South East Asia (SEA). We sort to find the status of artemisinin resistance and efficacy of different modalities of the current artemisinin-based combination therapies (ACTs). METHODS: We carried out a systematic search in 11 electronic databases to identify in vivo studies published between 2001 and 2017 that reported artemisinin resistance. This was then followed by A network meta-analysis to compare the efficacy of different ACTs. Quality assessment was performed using the Cochrane Risk of Bias (ROB) tool for randomized controlled trials and National Institute of Health (NIH) tool for cross-sectional studies. The study protocol was registered in PROSPERO under number CRD42018087574. RESULTS: With 8400 studies initially identified, 82 were eligible for qualitative and quantitative analysis. Artemisinin resistance was only reported in South East Asia. K13 mutation C580Y was the most abundant mutation associated with resistance having an abundance of 63.1% among all K13 mutations reported. Although the overall network meta-analysis had shown good performance of dihydroartemisinin piperaquine in the early years, a subgroup analysis of the recent years revealed a poor performance of the drug in relation to recrudescence, clinical failure and parasitological failure especially in the artemisinin resistant regions. CONCLUSION: With report of high resistance and treatment failure against the leading artemisinin combination therapy in South East Asia, it is imperative that a new drug or a formulation is developed before further spread of resistance.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Ásia Sudeste , Estudos Transversais , Quimioterapia Combinada , Humanos , Meta-Análise em Rede , Falha de Tratamento
5.
BMC Infect Dis ; 19(1): 1025, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31795967

RESUMO

BACKGROUND: Treatment for severe malaria must be prompt with effective parenteral antimalarial drugs for at least 24 h to achieve fast parasite clearance, and when the patient can tolerate oral therapy, treatment should be completed with effective artemisinin based combination therapy (ACT) for complete parasite clearance and to prevent recrudescence. We evaluated piperaquine concentration and malaria treatment outcomes among Ugandan children treated for severe malaria with intravenous artesunate (AS) or quinine (QN) plus dihydroartemisinin-piperaquine (DP), in Tororo District Hospital in Eastern Uganda. METHODS: Capillary blood piperaquine concentration data were obtained from a randomized clinical trial whose objective was to evaluate parasite clearance, 42-day parasitological treatment outcomes and safety, following treatment of severe malaria with intravenous AS or QN, plus artemether-lumefantrine or DP among children in Tororo District Hospital, in Eastern Uganda. RESULTS: Piperaquine concentration data from 150 participants who received DP were analyzed. Participants with unadjusted treatment failure had lower median day 7 capillary piperaquine concentration than those with treatment success (34.7 (IQR) (17.9-49.1) vs 66.7 (IQR) (41.8-81.9), p < 0.001), and lower than the recommended day 7 cut off level of 57 ng/mL. There was no difference in median capillary piperaquine concentrations among participants with re-infection and recrudescence (35.3 (IQR) (17.9-55.2) vs 34.8 (IQR) (18.1-45.1), p = 0.847). The risk of treatment failure was two times higher among children with low (< 57 ng/mL) day 7 capillary piperaquine concentration (relative risk: 2.1 CI 1.4-3.1), p < 0.001) compared to children with high day 7 capillary piperaquine concentrations (> 57 ng/mL). CONCLUSION: Considering the low day 7 concentrations of piperaquine reported in the patients studied here, we suggest to adopt the recently recommended higher dose of DP in young children or a prolonged 5-day dosing in children living in malaria endemic areas who have suffered an initial episode of severe malaria in order to achieve adequate drug exposures for effective post-treatment prophylactic effects. TRIAL REGISTRATION: The study was registered with the Pan African Clinical Trial Registry (PACTR201110000321348). Registered 7th October 2011.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Artesunato/uso terapêutico , Malária Falciparum/tratamento farmacológico , Quinina/uso terapêutico , Quinolinas/sangue , Quinolinas/uso terapêutico , Administração Intravenosa , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Artesunato/administração & dosagem , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Malária Falciparum/parasitologia , Masculino , Concentração Osmolar , Plasmodium falciparum/isolamento & purificação , Quinina/administração & dosagem , Quinolinas/administração & dosagem , Recidiva , Resultado do Tratamento , Uganda
6.
PLoS One ; 14(12): e0225882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856172

RESUMO

BACKGROUND: The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial drugs is a key component of malaria control and elimination. The published randomized trials that assessed comparisons of ACTs for treating uncomplicated falciparum malaria reported conflicting results in treatment efficacy. A network meta-analysis is an extension of pairwise meta-analysis that can synthesize evidence simultaneously from both direct and indirect treatment comparisons. The objective was to synthesize evidence on the comparative efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region. METHODS: Relevant randomized trials that assessed efficacy of antimalarial drugs for patients having uncomplicated falciparum malaria in Asian region were searched in health-related databases. We evaluated the methodological quality of the included studies with the Cochrane risk of bias tool. Main outcome was treatment success at day 28 as determined by the absence of parasiteamia. We performed network meta-analysis of the interventions in the trials, and assessed the overall quality of evidence using the GRADE approach. RESULTS: Seventeen randomized trials (n = 5043) were included in this network meta-analysis study. A network geometry was formed with 14 antimalarial treatment options such as artemether-lumefantrine (AL), artemisinin-piperaquine, artesunate-amodiaquine, artesunate-mefloquine (ASMQ), artesunate-chloroquine, artesunate-mefloquine home treatment, artesunate-mefloquine 2-day course, artesunate plus sulfadoxine-pyrimethamine, chloroquine, dihydroartemisinin-piperaquine (DHP), dihydroartemisinin-piperaquine home treatment, dihydroartemisinin-piperaquine 4-day course, dihydroartemisinin-piperaquine and added artesunate, sulfadoxine-pyrimethamine. A maximum number of trials included was DHP compared to ASMQ (n = 5). In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8). There is low certainty evidence due to limited number of studies and small trials. DISCUSSION/ CONCLUSIONS: The findings suggest the superiority of DHP (3-day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. For substantiation, well-designed larger trials from endemic countries are needed. In the light of benefit versus harm concept, future analysis with safety information is recommended.


Assuntos
Antimaláricos/uso terapêutico , Bases de Dados Factuais , Resistência a Medicamentos/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Antimaláricos/efeitos adversos , Ásia , Humanos , Malária Falciparum/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Nature ; 576(7786): 315-320, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31776516

RESUMO

The emergence and spread of drug-resistant Plasmodium falciparum impedes global efforts to control and eliminate malaria. For decades, treatment of malaria has relied on chloroquine (CQ), a safe and affordable 4-aminoquinoline that was highly effective against intra-erythrocytic asexual blood-stage parasites, until resistance arose in Southeast Asia and South America and spread worldwide1. Clinical resistance to the chemically related current first-line combination drug piperaquine (PPQ) has now emerged regionally, reducing its efficacy2. Resistance to CQ and PPQ has been associated with distinct sets of point mutations in the P. falciparum CQ-resistance transporter PfCRT, a 49-kDa member of the drug/metabolite transporter superfamily that traverses the membrane of the acidic digestive vacuole of the parasite3-9. Here we present the structure, at 3.2 Å resolution, of the PfCRT isoform of CQ-resistant, PPQ-sensitive South American 7G8 parasites, using single-particle cryo-electron microscopy and antigen-binding fragment technology. Mutations that contribute to CQ and PPQ resistance localize primarily to moderately conserved sites on distinct helices that line a central negatively charged cavity, indicating that this cavity is the principal site of interaction with the positively charged CQ and PPQ. Binding and transport studies reveal that the 7G8 isoform binds both drugs with comparable affinities, and that these drugs are mutually competitive. The 7G8 isoform transports CQ in a membrane potential- and pH-dependent manner, consistent with an active efflux mechanism that drives CQ resistance5, but does not transport PPQ. Functional studies on the newly emerging PfCRT F145I and C350R mutations, associated with decreased PPQ susceptibility in Asia and South America, respectively6,9, reveal their ability to mediate PPQ transport in 7G8 variant proteins and to confer resistance in gene-edited parasites. Structural, functional and in silico analyses suggest that distinct mechanistic features mediate the resistance to CQ and PPQ in PfCRT variants. These data provide atomic-level insights into the molecular mechanism of this key mediator of antimalarial treatment failures.


Assuntos
Microscopia Crioeletrônica , Resistência a Medicamentos/efeitos dos fármacos , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/ultraestrutura , Plasmodium falciparum/química , Proteínas de Protozoários/química , Proteínas de Protozoários/ultraestrutura , Cloroquina/metabolismo , Cloroquina/farmacologia , Resistência a Medicamentos/genética , Concentração de Íons de Hidrogênio , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Modelos Moleculares , Mutação , Plasmodium falciparum/genética , Plasmodium falciparum/ultraestrutura , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacologia
8.
BMC Infect Dis ; 19(1): 920, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664924

RESUMO

BACKGROUND: The only licensed malaria vaccine, RTS,S/AS01, has been developed for morbidity-control in young children. The potential impact on transmission of deploying such anti-infective vaccines to wider age ranges, possibly with co-administration of antimalarial treatment, is unknown. Combinations of existing malaria interventions is becoming increasingly important as evidence mounts that progress on reducing malaria incidence is stalling and threatened by resistance. METHODS: Malaria transmission and intervention dynamics were simulated using OpenMalaria, an individual-based simulation model of malaria transmission, by considering a seasonal transmission setting and by varying epidemiological and setting parameters such as transmission intensity, case management, intervention types and intervention coverages. Chemopreventive drugs and anti-infective vaccine efficacy profiles were based on previous studies in which model parameters were fitted to clinical trial data. These intervention properties were used to evaluate the potential of seasonal mass applications of preventative anti-infective malaria vaccines, alone or in combination with chemoprevention, to reduce malaria transmission, prevent resurgence, and/or reach transmission interruption. RESULTS: Deploying a vaccine to all ages on its own is a less effective intervention strategy compared to chemoprevention alone. However, vaccines combined with drugs are likely to achieve dramatic prevalence reductions and in few settings, transmission interruption. The combined mass intervention will result in lower prevalence following the intervention compared to chemoprevention alone and will increase chances of interruption of transmission resulting from a synergistic effect between both interventions. The combination of vaccine and drug increases the time before transmission resurges after mass interventions cease compared to mass treatment alone. Deploying vaccines and drugs together requires fewer rounds of mass intervention and fewer years of intervention to achieve the same public health impact as chemoprevention alone. CONCLUSIONS: Through simulations we identified a previously unidentified value of deploying vaccines with drugs, namely the greatest benefit will be in preventing and delaying transmission resurgence for longer periods than with other human targeted interventions. This is suggesting a potential role for deploying vaccines alongside drugs in transmission foci as part of surveillance-response strategies.


Assuntos
Antimaláricos/administração & dosagem , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Administração Massiva de Medicamentos , Vacinação em Massa , Modelos Teóricos , Estações do Ano , Adulto , Quimioprevenção/métodos , Criança , Pré-Escolar , Transmissão de Doença Infecciosa/prevenção & controle , Quimioterapia Combinada , Humanos , Lactente , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/imunologia , Prevalência
9.
PLoS Pathog ; 15(10): e1008086, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658303

RESUMO

Plasmodium parasites are the causative agents of malaria, a disease with wide public health repercussions. Increasing drug resistance and the absence of a vaccine make finding new chemotherapeutic strategies imperative. Components of the ubiquitin and ubiquitin-like pathways have garnered increased attention as novel targets given their necessity to parasite survival. Understanding how these pathways are regulated in Plasmodium and identifying differences to the host is paramount to selectively interfering with parasites. Here, we focus on Nedd8 modification in Plasmodium falciparum, given its central role to cell division and DNA repair, processes critical to Plasmodium parasites given their unusual cell cycle and requirement for refined repair mechanisms. By applying a functional chemical approach, we show that deNeddylation is controlled by a different set of enzymes in the parasite versus the human host. We elucidate the molecular determinants of the unusual dual ubiquitin/Nedd8 recognition by the essential PfUCH37 enzyme and, through parasite transgenics and drug assays, determine that only its ubiquitin activity is critical to parasite survival. Our experiments reveal interesting evolutionary differences in how neddylation is controlled in higher versus lower eukaryotes, and highlight the Nedd8 pathway as worthy of further exploration for therapeutic targeting in antimalarial drug design.


Assuntos
Proteína NEDD8/metabolismo , Plasmodium falciparum/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Antimaláricos/farmacologia , Linhagem Celular , Células HEK293 , Humanos , Hidrólise , Malária Falciparum/tratamento farmacológico , Malária Falciparum/patologia , Ubiquitinação/fisiologia
10.
PLoS Genet ; 15(10): e1008453, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31609965

RESUMO

Determining the genetic basis of fitness is central to understanding evolution and transmission of microbial pathogens. In human malaria parasites (Plasmodium falciparum), most experimental work on fitness has focused on asexual blood stage parasites, because this stage can be easily cultured, although the transmission of malaria requires both female Anopheles mosquitoes and vertebrate hosts. We explore a powerful approach to identify the genetic determinants of parasite fitness across both invertebrate and vertebrate life-cycle stages of P. falciparum. This combines experimental genetic crosses using humanized mice, with selective whole genome amplification and pooled sequencing to determine genome-wide allele frequencies and identify genomic regions under selection across multiple lifecycle stages. We applied this approach to genetic crosses between artemisinin resistant (ART-R, kelch13-C580Y) and ART-sensitive (ART-S, kelch13-WT) parasites, recently isolated from Southeast Asian patients. Two striking results emerge: we observed (i) a strong genome-wide skew (>80%) towards alleles from the ART-R parent in the mosquito stage, that dropped to ~50% in the blood stage as selfed ART-R parasites were selected against; and (ii) repeatable allele specific skews in blood stage parasites with particularly strong selection (selection coefficient (s) ≤ 0.18/asexual cycle) against alleles from the ART-R parent at loci on chromosome 12 containing MRP2 and chromosome 14 containing ARPS10. This approach robustly identifies selected loci and has strong potential for identifying parasite genes that interact with the mosquito vector or compensatory loci involved in drug resistance.


Assuntos
Interações Hospedeiro-Parasita/genética , Estágios do Ciclo de Vida/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Animais , Anopheles/parasitologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Mapeamento Cromossômico , Modelos Animais de Doenças , Resistência a Medicamentos/genética , Feminino , Frequência do Gene , Loci Gênicos , Humanos , Malária Falciparum/tratamento farmacológico , Masculino , Camundongos , Mosquitos Vetores/parasitologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Polimorfismo de Nucleotídeo Único , Proteínas Ribossômicas/genética , Seleção Genética , Quimeras de Transplante
11.
BMC Infect Dis ; 19(1): 872, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640574

RESUMO

BACKGROUND: Drug resistant malaria is a growing concern in the Democratic Republic of the Congo (DRC), where previous studies indicate that parasites resistant to sulfadoxine/pyrimethamine or chloroquine are spatially clustered. This study explores longitudinal changes in spatial patterns to understand how resistant malaria may be spreading within the DRC, using samples from nation-wide population-representative surveys. METHODS: We selected 552 children with PCR-detectable Plasmodium falciparum infection and identified known variants in the pfdhps and pfcrt genes associated with resistance. We compared the proportion of mutant parasites in 2013 to those previously reported from adults in 2007, and identified risk factors for carrying a resistant allele using multivariate mixed-effects modeling. Finally, we fit a spatial-temporal model to the observed data, providing smooth allele frequency estimates over space and time. RESULTS: The proportion of co-occurring pfdhps K540E/A581G mutations increased by 16% between 2007 and 2013. The spatial-temporal model suggests that the spatial range of the pfdhps double mutants expanded over time, while the prevalence and range of pfcrt mutations remained steady. CONCLUSIONS: This study uses population-representative samples to describe the changing landscape of SP resistance within the DRC, and the persistence of chloroquine resistance. Vigilant molecular surveillance is critical for controlling the spread of resistance.


Assuntos
Antimaláricos/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Adolescente , Adulto , Álcool Desidrogenase/genética , Cloroquina/uso terapêutico , Estudos Transversais , República Democrática do Congo/epidemiologia , Combinação de Medicamentos , Resistência a Medicamentos/genética , Frequência do Gene , Humanos , Estudos Longitudinais , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Mutação , Plasmodium falciparum/genética , Prevalência , Proteínas de Protozoários/genética , Pirimetamina/uso terapêutico , Análise Espaço-Temporal , Sulfadoxina/uso terapêutico , Adulto Jovem
12.
Int J Mol Sci ; 20(20)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615031

RESUMO

Transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is initiated by specialized sexual cells, the gametocytes. In the human, gametocytes are formed in response to stress signals and following uptake by a blood-feeding Anopheles mosquito initiate sexual reproduction. Gametocytes need to fine-tune their gene expression in order to develop inside the mosquito to continue life-cycle progression. Previously, we showed that post-translational histone acetylation controls gene expression during gametocyte development and transmission. However, the role of histone methylation remains poorly understood. We here use the histone G9a methyltransferase inhibitor BIX-01294 to investigate the role of histone methylation in regulating gene expression in gametocytes. In vitro assays demonstrated that BIX-01294 inhibits intraerythrocytic replication with a half maximal inhibitory concentration (IC50) of 13.0 nM. Furthermore, BIX-01294 significantly impairs gametocyte maturation and reduces the formation of gametes and zygotes. Comparative transcriptomics between BIX-01294-treated and untreated immature, mature and activated gametocytes demonstrated greater than 1.5-fold deregulation of approximately 359 genes. The majority of these genes are transcriptionally downregulated in the activated gametocytes and could be assigned to transcription, translation, and signaling, indicating a contribution of histone methylations in mediating gametogenesis. Our combined data show that inhibitors of histone methylation may serve as a multi-stage antimalarial.


Assuntos
Células Germinativas/crescimento & desenvolvimento , Histona-Lisina N-Metiltransferase/genética , Malária Falciparum/genética , Plasmodium falciparum/genética , Animais , Anopheles/efeitos dos fármacos , Anopheles/parasitologia , Antimaláricos/metabolismo , Antimaláricos/uso terapêutico , Azepinas/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células Germinativas/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Quinazolinas/farmacologia
13.
Rev Soc Bras Med Trop ; 52: e20190163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618306

RESUMO

Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated malaria. Currently, there appears to be a downward trend in the efficacy of ACT in some parts of sub-Saharan Africa because some patients have been positive for Plasmodium parasite 3 days after artemether-lumefantrine treatment. We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.


Assuntos
Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Adulto , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Adulto Jovem
14.
Korean J Parasitol ; 57(4): 369-377, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31533403

RESUMO

Artemisinin-based combination therapy (ACT) resistance is widespread throughout the Greater Mekong Subregion. This raises concern over the antimalarial treatment in Thailand since it shares borders with Cambodia, Laos, and Myanmar where high ACT failure rates were reported. It is crucial to have information about the spread of ACT resistance for efficient planning and treatment. This study was to identify the molecular markers for antimalarial drug resistance: Pfkelch13 and Pfmdr1 mutations from 5 provinces of southern Thailand, from 2012 to 2017, of which 2 provinces on the Thai- Myanmar border (Chumphon and Ranong), one on Thai-Malaysia border (Yala) and 2 from non-border provinces (Phang Nga and Surat Thani). The results showed that C580Y mutation of Pfkelch13 was found mainly in the province on the Thai-Myanmar border. No mutations in the PfKelch13 gene were found in Surat Thani and Yala. The Pfmdr1 gene isolated from the Thai-Malaysia border was a different pattern from those found in other areas (100% N86Y) whereas wild type strain was present in Phang Nga. Our study indicated that the molecular markers of artemisinin resistance were spread in the provinces bordering along the Thai-Myanmar, and the pattern of Pfmdr1 mutations from the areas along the international border of Thailand differed from those of the non-border provinces. The information of the molecular markers from this study highlighted the recent spread of artemisinin resistant parasites from the endemic area, and the data will be useful for optimizing antimalarial treatment based on regional differences.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Marcadores Genéticos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/genética , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Artemisininas/administração & dosagem , Artemisininas/uso terapêutico , Sequência de Bases , DNA de Protozoário/química , Combinação de Medicamentos , Resistência a Medicamentos/genética , Genes MDR/genética , Humanos , Repetição Kelch/genética , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Reação em Cadeia da Polimerase , Tailândia
15.
Malar J ; 18(1): 267, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31477109

RESUMO

Parasite resistance against anti-malarial drugs is a major threat to the ongoing malaria control and elimination strategies. This is especially true since resistance to the currently recommended artemisinins and partner drugs has been confirmed in South East Asia (SEA) and new anti-malarial compounds are not expected to be available in the near future. Spread from SEA or independent emergence of artemisinin resistance in sub-Saharan Africa (SSA) could reverse the achievements in malaria control that have been attained in the past two decades and derail the ongoing elimination strategies. The current surveillance of clinical efficacy and resistance to anti-malarial drugs is based on efficacy trials to assess the clinical performance of anti-malarials, in vivo/ex vivo assessment of parasite susceptibility to anti-malarials and prevalence of known molecular markers of drug resistance. Whereas clinical efficacy trials are restricted by cost and the complex logistics of patient follow-up, molecular detection of genetic mutations associated with resistance or reduced susceptibility to anti-malarials is by contrast a simple and powerful tool for early detection and monitoring of the prevalence of resistant parasites at population level. This provides needed information before clinical failure emerges, allowing policy makers to anticipate problems and respond. The various methods previously used in detection of molecular markers of drug resistance share some limitations: low-throughput, and high costs per sample and demanding infrastructure. However, recent technological advances including next-generation sequencing (NGS) methodologies promise greatly increased throughput and reduced costs, essentially providing unprecedented potential to address different research and operational questions of relevance for drug policy. This review assesses the potential role of NGS to provide comprehensive information that could guide drug policies in malaria endemic countries and looks at the foreseeable challenges facing the establishment of NGS approaches for routine surveillance of parasite resistance to anti-malarials in SSA.


Assuntos
Antimaláricos/uso terapêutico , Controle de Doenças Transmissíveis/legislação & jurisprudência , Resistência a Medicamentos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Plasmodium falciparum/genética , Formulação de Políticas , África ao Sul do Saara , Controle de Doenças Transmissíveis/métodos , Quimioterapia Combinada , Saúde Global/legislação & jurisprudência , Saúde Global/normas , Legislação de Medicamentos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos
16.
Ghana Med J ; 53(2): 109-116, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31481806

RESUMO

Background: Malaria is a public health problem compounded with a widespread emergence of drug-resistant Plasmodium falciparum which necessitated the formulation of a new antimalarial drug policy (AMP). Objective: This study was designed to assess adherence to the policy among physicians in health facilities in Delta state, Nigeria. Design: Cross-sectional, analytic study. Data were collected with a semi-structured questionnaire. Setting: Two secondary and one tertiary health facilities in Delta State, Nigeria. Participants: Physicians selected with a simple random technique from the facilities. Main outcome measures: Prescribing pattern of antimalarial drugs and adherence to WHO treatment guideline among doctors. Results: Majority (90.8%) of respondents believed the antimalarial policy (AMP) should be strictly adhered to, although three-fifth (61.0%) of them rated its performance as poor. The level of adherence to the national antimalarial drug policy was high (78.5%) as most doctors prescribed Arthemeter-Lumefantrine, AL for uncomplicated malaria however barely two-fifth (35.4%) adhered to prescribing injectable Artesunate for complicated malaria. AL, (71.9%) was the most prescribed antimalarial drug for uncomplicated malaria The most prescribed antimalarial drugs for complicated malaria was artesunate (40.0%) followed by quinine (27.6%) and artemether (26.7%); although, chloroquine was also prescribed. Conclusion: The level of adherence to AMP among doctors was sub-optimal. Continuous education of doctors on the new AMP is needed to achieve malarial control. Funding: No funding was received for this study.


Assuntos
Antimaláricos/uso terapêutico , Resistência Microbiana a Medicamentos , Fidelidade a Diretrizes , Malária Falciparum/tratamento farmacológico , Guias de Prática Clínica como Assunto , Adulto , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artesunato/uso terapêutico , Cloroquina/uso terapêutico , Feminino , Política de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria , Plasmodium falciparum , Padrões de Prática Médica , Quinina/uso terapêutico , Inquéritos e Questionários , Adulto Jovem
17.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374989

RESUMO

This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1-6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (11-16) and evaluated their activity against both the hepatic and erythrocytic stages of Plasmodium. Our results have shown that PQ fumardiamides (1-6) exert both higher activity against P. berghei hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (11-16). The favourable cytotoxicity profile of the most active compounds, 5 and 6, was corroborated by assays performed on human cells (human breast adenocarcinoma (MCF-7) and non-tumour embryonic kidney cells (HEK293T)), even when glucose-6-phosphate dehydrogenase (G6PD) was inhibited. The activity of CQ fumardiamides on P. falciparum erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain PfDd2, but lower than CQ when tested on the CQ-sensitive strain Pf3D7. In addition, both sets of compounds showed favourable drug-like properties. Hence, quinoline fumardiamides could serve as a starting point towards the development of safer and more effective antiplasmodial agents.


Assuntos
Antimaláricos/química , Cloroquina/química , Malária Falciparum/tratamento farmacológico , Primaquina/química , Antimaláricos/farmacologia , Cloroquina/farmacologia , Eritrócitos/efeitos dos fármacos , Células HEK293 , Humanos , Malária Falciparum/parasitologia , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Primaquina/farmacologia , Relação Estrutura-Atividade
18.
Science ; 365(6455): 813-816, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31439796

RESUMO

Understanding genomic variation and population structure of Plasmodium falciparum across Africa is necessary to sustain progress toward malaria elimination. Genome clustering of 2263 P. falciparum isolates from 24 malaria-endemic settings in 15 African countries identified major western, central, and eastern ancestries, plus a highly divergent Ethiopian population. Ancestry aligned to these regional blocs, overlapping with both the parasite's origin and with historical human migration. The parasite populations are interbred and shared genomic haplotypes, especially across drug resistance loci, which showed the strongest recent identity-by-descent between populations. A recent signature of selection on chromosome 12 with candidate resistance loci against artemisinin derivatives was evident in Ghana and Malawi. Such selection and the emerging substructure may affect treatment-based intervention strategies against P. falciparum malaria.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Etiópia/epidemiologia , Loci Gênicos , Gana/epidemiologia , Haplótipos , Humanos , Malária Falciparum/tratamento farmacológico , Malaui/epidemiologia , Plasmodium falciparum/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Seleção Genética
19.
Cell Host Microbe ; 26(1): 35-47, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295423

RESUMO

Intensified treatment and control efforts since the early 2000s have dramatically reduced the burden of Plasmodium falciparum malaria. However, drug resistance threatens to derail this progress. In this review, we present four antimalarial resistance case studies that differ in timeline, technical approaches, mechanisms of action, and categories of resistance: chloroquine, sulfadoxine-pyrimethamine, artemisinin, and piperaquine. Lessons learned from prior losses of treatment efficacy, drug combinations, and control strategies will help advance mechanistic research into how P. falciparum parasites acquire resistance to current first-line artemisinin-based combination therapies. Understanding resistance in the clinic and laboratory is essential to prolong the effectiveness of current antimalarial drugs and to optimize the pipeline of future medicines.


Assuntos
Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Quimioterapia Combinada/métodos , Humanos
20.
Malar J ; 18(1): 225, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277713

RESUMO

BACKGROUND: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections. METHODS: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model. RESULTS: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (ρ): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [ρ: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold. CONCLUSIONS: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.


Assuntos
Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Humanos , Meta-Análise em Rede , Reação em Cadeia da Polimerase , Recidiva , Análise de Regressão , Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA